Customization of Aneurysm Scaffold Geometries for In Vitro Tissue-Engineered Blood Vessel Mimics to Use as Models for Neurovascular Device Testing

Cerebral aneurysms occur due to the ballooning of blood vessels in the brain. Rupture of aneurysms can cause a subarachnoid hemorrhage, which, if not fatal, can cause permanent neurologic deficits. Minimally invasive neurovascular devices, such as embolization coils and flow diverters, are methods of treatment utilized to prevent aneurysm rupture. The rapidly growing market for neurovascular devices necessitates the development of accurate aneurysm models for preclinical testing. In vivo models, such as the rabbit elastase model, are commonly chosen for preclinical device testing; however, these studies are expensive, and aneurysm geometries are difficult to control and often do not replicate the variety of geometries found in clinical cases. A promising alternative for preclinical testing of neurovascular devices is an aneurysm blood vessel mimic (aBVM), which is an in vitro tissue-engineered model of a human blood vessel composed of an electrospun scaffold with an aneurysm geometry and human vascular cells. Previous work in the Cal Poly Tissue Engineering Lab has established a process for creating different aneurysm scaffolds based on the shape of different geometries, and this work aimed to further advance these aneurysm geometries in order to enhance the versatility of the in vitro model. The overall goal of this thesis was to customize the aBVM model through variations of different dimensions and to validate the scaffold variations for neurovascular device testing. First, a literature review was performed to identify critical ranges of aneurysm neck diameters and heights that are commonly seen in rabbit elastase models and in human clinical settings in order to set a foundation for creating new geometries. Based on the results, aneurysm geometries with varying neck sizes and heights were modeled and molded, and scaffolds were fabricated through electrospinning. Methods were developed to characterize scaffolds with internal measurements through imaging techniques using a scanning electron microscope. To validate these scaffolds for use as aBVMs for neurovascular device testing, constructs were created by dual-sodding human endothelial cells and smooth muscle cells into scaffolds with varying neck sizes. Finally, flow diverters were deployed in constructs with varying neck sizes in order to evaluate feasibility and initial healing. Customized aneurysm scaffolds can eventually be used with a variety of device studies for screening of neurovascular devices or as a predecessor for in vivo preclinical testing

The contemporary endovascular treatment of intracranial aneurysms

The first endovascular treatment of intracranial aneurysms began with simple coiling in 1991. Ever since, it has developed significantly, and endovascular treatment is now the first choice for most intracranial aneurysms. However, some intracranial aneurysms such as wide-necked, blood-blister-like, fusiform and dissecting intracranial aneurysms are not suitable for simple coiling. In 2008, intraluminal flow diversion was introduced for uncoilable saccular intracranial aneurysms of the internal carotid artery, and since then, the indications of intraluminal flow diversion have expanded to complex aneurysms like blister-like, dissecting, and fusiform intracranial aneurysms. In 2010, intrasaccular flow disruption was introduced with the Woven EndoBridge (WEB) for the treatment of naïve wide-necked bifurcation aneurysms. Several studies have shown the safety and efficacy of flow diverters and WEB in the treatment of intracranial aneurysms. In our study the safety and efficacy of the WEB and flow diverters were assessed in Finnish population. Furthermore, we identified and analysed the factors influencing radiological outcomes after the contemporary endovascular treatments. A rate of 90% adequate radiological outcomes can be achieved in the treatment of naïve and recurrent wide-necked intracranial aneurysms with the WEB. No rupture or re-rupture observed after the WEB treatment. The flow diverters can provide a high occlusion rate for elective and acutely ruptured intracranial aneurysms. However, a 45% rate of complications was observed in flow diversion for acutely ruptured intracranial aneurysms. The WEB for wide-necked intracranial aneurysms including wide-necked recurrent intracranial aneurysms appears to be safe and efficient, and is a valuable alternative when the conventional methods are not amenable. The aneurysm morphology and size seem to influence the radiological outcomes after the WEB treatment. Flow diverters provides high occlusion rates. However, the flow diversion of acutely ruptured intracranial aneurysms carries a high rate of complications. Flow diversion can be justified as a last-resort option when other endovascular methods are not suitable for acutely ruptured intracranial aneurysms.Aivovaltimoaneurysmien nykyaikainen suonensisäinen hoito Aivovaltimoaneurysma hoidettiin koiliembolisaatiolla onnistuneesti ensimmäisen kerran vuonna 1991, ja siitä lähtien endovaskulaariset tekniikat ovat kehittyneet merkittävästi. Endovaskulaarinen menetelmä onkin nykyään ensisijainen valinta useimpien aneurysmien hoitoon. Koska rakkulamaiset, dissekoivat ja fusiformiset aneurysmat ovat vaikeita hoitaa tavanomaisilla endovaskulaarisilla menetelmillä, vaikeahoitoisia aneurysmia varten otettiin vuonna 2008 käyttöön flow diverter -stentit. Niiden alkuperäinen käyttöaihe oli sisemmän kaulavaltimon jättianeurysmien hoito; nyt käyttöaiheet ovat laajentuneet niin rakkulamaisten kuin dissekoivien aneurysmien hoitoon. Intrasakkulaarinen laite Woven Endobridge (WEB) kehitettiin vuonna 2010 leveäkaulaisten aivovaltimoaneurysmien hoitoon. Useat tutkimukset ovat osoittaneet sekä flow diverter -stentin sekä WEB:in turvallisuuden ja tehokkuuden aivoaneurysmien hoidossa. Tutkimuksessa arvioitiin WEB ja flow diverter -hoidon turvallisuutta ja tehokkuutta Suomessa. Erityistä huomiota kiinnitettiin tekijöihin, jotka ennustavat radiologisia tuloksia nykyaikaisen hoidon jälkeen. Tutkimuksella todettiin, että WEB-hoidolla voidaan saavuttaa 90%:sti lähes täydellinen radiologinen hoitotulos. WEB-hoidon jälkeen aneurysmien puhkeamista ei havaittu. Flow diverter -hoidolla saavutetaan 90%:sti täydellinen tai lähes täydellinen radiologinen tulos, mutta 45%:lla potilaista esiintyy jokin flow diverter -hoitoon liittyvä komplikaatio akuutisti puhjenneiden aneurymien hoidossa. WEB on tehokas menetelmä sekä uusien että uusiutuneiden leveäkaulaisten aneurysmien hoidossa. Se on käyttökelpoinen silloin, kun perinteiset menetelmät eivät riitä. Aneurysman muoto ja koko vaikuttavat WEB:in hoitotuloksiin. Flow diverterit mahdollistavat hyvän radiologisen hoitotuloksen akuutisti repeytyneissä aivoaneurysmissa. Niiden flow diverter -hoitoon liittyy kuitenkin huomattavan korkea komplikaatioriski, mutta mikäli muu menetelmä ei potilaan akuutisti puhjenneen aneurysman hoitoon sovellu, sitä voidaan viimeisenä hoitomuotona perustellusti käyttää

Understanding the role of hemodynamics in the initiation, progression, rupture, and treatment outcome of cerebral aneurysm from medical iamge-based computational studies

About a decade ago, the first image-based computational hemodynamic studies of cerebral aneurysms were presented. Their potential for clinical applications was the results of a right combination of medical image processing, vascular reconstruction, and grid generation techniques used to reconstruct personalziaed domains for computational fluid and solid dynamics solvers and data analysis and visualization techniques. A considerable number of studies have captivated the attention of clinicians, neurosurgeons, and neuroradiologists, who realized the ability of those tools to help in understanding the role played by hemodynamics in the natural history and management of intracranial aneurysms. This paper intends to summarize the most relevant results in the filed reported during the last years.Fil: Castro, Marcelo Adrian. Universidad Tecnológica Nacional. Facultad Regional Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

The Hemodynamics of Aneurysms Treated with Flow-Diverting Stents Considering both Stent and Aneurysm/Artery Geometries

Flow diverting stents are deployed to reduce the blood flow into the aneurysm, which would thereby induce thrombosis in the aneurysm sac; the stents prevent its rupture. The present study aimed to examine and quantify the impacts of different flow stents on idealized configurations of the cerebral artery. In our study, we considered a spherical sidewall aneurysm located on curved and tortuous idealized artery vessels and three stents with different porosities (70, 80 and 90%) for deployment. Using computational fluid dynamics, the local hemodynamics in the presence and absence of the stents were simulated, respectively, under the assumption that the blood flow was unsteady and non-Newtonian. The hemodynamic parameters, such as the intra-aneurysmal flow, velocity field and wall shear stress and its related indices, were examined and compared among the 12 cases simulated. The results illustrated that with the stent deployment, the intra-aneurysmal flow and the wall shear stress and its related indices were considerably modified depending on both stent and aneurysm/artery geometries, and that the intra-aneurysmal relative residence time increased rapidly with decreasing stent porosity in all the vessel configurations. These results also inform the rationale for selecting stents for treating aneurysms of different configurations

In-silico clinical trials for assessment of intracranial flow diverters

In-silico trials refer to pre-clinical trials performed, entirely or in part, using individualised computer models that simulate some aspect of drug effect, medical device, or clinical intervention. Such virtual trials reduce and optimise animal and clinical trials, and enable exploring a wider range of anatomies and physiologies. In the context of endovascular treatment of intracranial aneurysms, in-silico trials can be used to evaluate the effectiveness of endovascular devices over virtual populations of patients with different aneurysm morphologies and physiologies. However, this requires (i) a virtual endovascular treatment model to evaluate device performance based on a reliable performance indicator, (ii) models that represent intra- and inter-subject variations of a virtual population, and (iii) creation of cost-effective and fully-automatic workflows to enable a large number of simulations at a reasonable computational cost and time. Flow-diverting stents have been proven safe and effective in the treatment of large wide-necked intracranial aneurysms. The presented thesis aims to provide the ingredient models of a workflow for in-silico trials of flow-diverting stents and to enhance the general knowledge of how the ingredient models can be streamlined and accelerated to allow large-scale trials. This work contributed to the following aspects: 1) To understand the key ingredient models of a virtual treatment workflow for evaluation of the flow-diverter performance. 2) To understand the effect of input uncertainty and variability on the workflow outputs, 3) To develop generative statistical models that describe variability in internal carotid artery flow waveforms, and investigate the effect of uncertainties on quantification of aneurysmal wall shear stress, 4) As part of a metric to evaluate success of flow diversion, to develop and validate a thrombosis model to assess FD-induced clot stability, and 5) To understand how a fully-automatic aneurysm flow modelling workflow can be built and how computationally inexpensive models can reduce the computational costs

Virtual endovascular treatment of intracranial aneurysms: models and uncertainty

Virtual endovascular treatment models (VETMs) have been developed with the view to aid interventional neuroradiologists and neurosurgeons to pre-operatively analyze the comparative efficacy and safety of endovascular treatments for intracranial aneurysms. Based on the current state of VETMs in aneurysm rupture risk stratification and in patient-specific prediction of treatment outcomes, we argue there is a need to go beyond personalized biomechanical flow modeling assuming deterministic parameters and error-free measurements. The mechanobiological effects associated with blood clot formation are important factors in therapeutic decision making and models of post-treatment intra-aneurysmal biology and biochemistry should be linked to the purely hemodynamic models to improve the predictive power of current VETMs. The influence of model and parameter uncertainties associated to each component of a VETM is, where feasible, quantified via a random-effects meta-analysis of the literature. This allows estimating the pooled effect size of these uncertainties on aneurysmal wall shear stress. From such meta-analyses, two main sources of uncertainty emerge where research efforts have so far been limited: (1) vascular wall distensibility, and (2) intra/intersubject systemic flow variations. In the future, we suggest that current deterministic computational simulations need to be extended with strategies for uncertainty mitigation, uncertainty exploration, and sensitivity reduction techniques. WIREs Syst Biol Med 2017, 9:e1385. doi: 10.1002/wsbm.138

Pathobiology of healing response after endovascular treatment of intracranial aneurysms : Paradigm shift from lumen to wall oriented therapy

Background and Purpose: Subarachnoid hemorrhage attributable to saccular intracranial aneurysm (IA) rupture is a devastating disease leading to stroke, permanent neurological damage and death. Despite rapid advances in the development of endovascular treatment (EVT), complete and long lasting IA occlusion remains a challenge, especially in complexly shaped and large-sized aneurysms. Intraluminal thrombus induced by EVT may recanalize. The biological mechanisms predisposing IA to recanalize and grow are not yet fully understood, and the role of mural cell loss in these processes remains unclear. To elucidate these processes, animal models featuring complex aneurysm architecture and aneurysm models with different wall conditions (such as mural cell loss) are needed. Materials and Methods: Complex bilobular, bisaccular and broad-neck venous pouch aneurysms were microsurgically formed at artificially created bifurcations of both common carotid arteries in New Zealand rabbits. Sidewall aneurysms were microsurgically created on the abdominal aorta in Wistar rats. Some sidewall aneurysms were decellularized with sodium dodecyl sulfate. Thrombosis was induced using direct injection of a fibrin polymer into the aneurysm. CM-Dil-labeled syngeneic smooth muscle cells were injected into fibrin embolized aneurysms. The procedures were followed up with two-dimensional intra-arterial digital subtraction angiography, contrast-enhanced serial magnetic resonance angiographies, endoscopy, optical projection tomography, histology and immunohistochemistry. Results: Aneurysm and parent vessel patency of large aneurysms with complex angioarchitecture was 90% at one month and 86% at one year follow-up in the bifurcation rabbit model. Perioperative and one month postoperative mortality and morbidity were 0% and 9%. Mean operation time in the rat model was less than one hour and aneurysm dimensions proved to be highly standardized. Significant growth, dilatation or rupture of the experimental aneurysms was not observed, with a high overall patency rate of 86% at three week follow-up. Combined surgery-related mortality and morbidity was 9%. Decellularized aneurysms demonstrated a heterogeneous pattern of thrombosis, thrombus recanalization and growth, with ruptures in the sidewall rat model. Aneurysms with intraluminal local cell replacement at the time of thrombosis developed better neointima, showed less recurrence or growth and no ruptures. Growing and ruptured aneurysms demonstrated marked adventitial fibrosis and inflammation, complete wall disruption and increased neutrophil accumulation in unorganized luminal thrombus. Conclusions: Creation of complex venous pouch bifurcation aneurysms in the rabbit is feasible, with low morbidity, mortality and high short-term and long-term aneurysm patency. They represent a promising approach for in vivo animal testing of novel endovascular therapies. The sidewall aneurysm rat model is a quick and consistent method to create standardized aneurysms. Aneurysms missing mural cells are incapable of organizing a luminal thrombus, leading to aneurysm recanalization and increased inflammatory reactions. These, in turn, result in severe wall degeneration, aneurysm growth and eventual rupture. The results of the presented studies suggest that the biologically active luminal thrombus drives the healing process towards destructive wall remodeling and aneurysm rupture. Local smooth muscle cell transplantation compensates for mural cell loss and reduces recurrence, growth and rupture rate in a sidewall aneurysm rat model.Aivovaltimopullistuman repeämisestä johtuva lukinkalvonalinen verenvuoto (subaraknoidaalivuoto, SAV) on äkillinen ja raju kallonsisäinen verenvuoto joka tapahtuu noin tuhannelle henkilölle suomessa per vuosi. SAV aiheuttaa pysyvän neurologisen haitan tai kuoleman valtaosalle potilaista. Aivovaltimopullistumia voidaan hoitaa joko mikrokirurgisella leikkauksella tai tukkimalla pullistuma suonensisäisesti (endovaskulaarinen hoito). Suonesisäiset hoitomenetelmät ovat viime vuosikymmeninä kehittyneet merkittävästi, mutta edelleen osaa pullistumista ei voida tällä menetelmällä hoitaa ja ajoittain hoidon tulos ei ole pitkällä aikavälillä pysyvä. Suonensisäisten hoitomenetelmien jatkokehittämiseksi tarvitaan enemmän tietoa aivovaltimopullistuman seinämässä tapahtuvista biologisista mekanismeista ja realistisempiä kokeellisia malleja, mukaan lukien koe-eläinmalleja, joissa hoitomenetelmiä voidaan testata. Tässä väitöskirjassa on syvennytty tutkimaan kahta eri koe-eläinmallia, kani- ja rottamallia. Väitöskirjassa osoitetaan että mallit soveltuvat suonensisäisten hoitomenetelmien testaamiseen. Malleissa on kyetty realistisella tavalla mallintamaan todellisen aivovaltimopullistuman eri rappeutuneisuusasteita ja saatu merkittävää lisätietoa siitä miten pullistuman seinämän biologiset tapahtumat joko vahvistavat seinämää tai altistavat seinämän repeämiselle

Complex Internal Carotid Artery Aneurysms

Complex intracranial aneurysms represent vascular lesions with attributes complicating their treatment. Giant intracranial aneurysms (GIA; ≥25 mm) are a rare subgroup of complex aneurysms with a particularly poor natural history. Due to their large size, giant aneurysms often present with cranial nerve dysfunctions. In this retrospective study, we aimed to provide a comprehensive description of the anatomical features of giant aneurysms in the internal carotid artery (ICA). Complex aneurysms are often difficult to approach directly, necessitating indirect treatment strategies. We therefore analysed a case series of bypass surgery and flow diversion in relation to the execution and outcomes in different segments of the ICA. All patients were admitted to the Helsinki University Hospital and for the analyses they were retrospectively recalled from the aneurysm database. For the series of giant aneurysms, we identified 125 patients with 129 GIAs (50 aneurysms in the ICA), from 1987 to 2007. For the series of bypass surgeries, included were 39 patients with 41 complex ICA aneurysms that were treated between 1998 and 2016. For the series of flow diversions, 62 patients with 76 ICA aneurysms were included from 2014 to 2019. In the treatment-oriented series, we analysed the internal carotid artery in segments, as this dictates the selection of treatment strategy. All the imaging studies and medical records were reviewed for relevant features in relation to aneurysms, complications and patient outcomes. The ICA was the most frequent location for GIAs in the cerebral arteries (39%) and most of these aneurysms were located specifically in the cavernous ICA segment (42%). Half of all GIAs presented mainly with symptoms of mass effect (50%). The cavernous GIAs were only rarely ruptured (10%) in contrary to the supraclinoid GIAs (36%). In general, wall calcification and intraluminal thrombosis were more seldom diagnosed in ruptured than in unruptured GIAs. In treatment of the complex ICA aneurysms with bypass procedures, the strategic goal of aneurysm treatment was achieved in 95% of cases (occlusion, 83%; flow modification, 12%). With flow diversion of the ICA aneurysms, 61% of aneurysms were occluded at 6-month follow-up and 69% at the latest follow-up. In both groups of treatment, the cavernous aneurysms became occluded slightly more often than the aneurysms in the supraclinoid region. Posttreatment large-scale strokes were rare (3-6%), but minor complications were seen more often. The pretreatment cranial nerve dysfunctions improved only moderately at best (cranial nerve-specific improvement rate of up to 60%). Respectively in groups of bypass and flow diversion, 74% and 85% of patients with unruptured aneurysms had favourable outcome at the latest follow-up. In both groups, only 25% of patients having unruptured aneurysms and presenting with poor functional status improved significantly to having a favourable outcome. The ICA is the most common location for GIAs and patients often present with symptoms of mass effect. Indirect treatment of complex ICA aneurysms with bypass procedures or flow diversion is feasible. Major treatment-related complications are rare, but minor complications occur at a non-negligible rate. Cranial nerve dysfunctions improve only in a proportion of patients. Lately, flow diverters have taken over the treatment of many complex ICA aneurysms, but the best treatment strategy should be assessed on a case-by-case basis, taking into consideration the burden of complex features of these aneurysms.Komplekseilla kallonsisäisillä aivovaltimopullistumilla eli aneurysmilla on ominaisuuksia, jotka tekevät aneurysmien hoidosta erityisen vaikeaa. Yhden alaryhmän muodostavat jättianeurysmat (≥25 mm), joilla on hoitamattomana erityisen korkea riski aiheuttaa aneurysmille tyypillinen hengenvaarallinen lukinkalvonalainen aivoverenvuoto. Kokonsa takia jättianeurysmat voivat tulla diagnosoiduksi myös esimerkiksi viereisten hermorakenteiden toimintahäiriöitä aiheuttaessaan. Kaikkiaan kompleksit aneurysmat, kuten jättianeurysmat, ovat harvinaisia ja siten niistä julkaistut aiemmat sarjat ovat olleet pääasiallisesti pieniä. Tässä retrospektiivisessä tutkimuksessa tavoitteemme oli seikkaperäisesti kuvailla sisemmän kaulavaltimon alueella sijainneiden jättianeurysmien anatomisia ominaisuuksia. Toisaalta kompleksien aneurysmien hoitamiseksi tarvitaan usein epäsuoria menetelmiä aneurysman sulkemiseksi verenkierrosta. Tämän takia analysoimme myös aivovaltimo-ohitusleikkausten sekä suonensisäisten virtausohjureiden (flow diverter) hoidolliset tulokset sisemmän kaulavaltimon aneurysmien osalta. Kaikki tutkimukseen sisällytetyt potilaat olivat olleet hoidossa HUS Helsingin yliopistollisessa sairaalassa, ja potilastiedot haettiin sarjoittain aneurysmarekisteristä vuosien 1989 ja 2019 väliseltä ajalta. Kaikki kuvantamistutkimukset sekä potilastiedot analysoitiin aneurysmiin, hoitotuloksiin ja hoidon komplikaatioihin liittyvien olennaisten tietojen osalta. Tutkimuksessamme totesimme, että sisempi kaulavaltimo on yleisin sijainti aivovaltimoiden jättianeurysmille ja tässä sijainnissa potilailla on usein aneurysman aiheuttamia aivohermo-oireita näkökyvyn häiriön muodossa. Epäsuora kompleksien aneurysmien hoito aivovaltimo-ohitteilla tai virtausohjureilla on toteuttamiskelpoista ja suurin osa aneurysmista sulkeutui seurannan aikana, mutta parhaimmillaan vain noin puolessa tapauksista aivohermo-oireet lievittyivät. Vakavat hoitoon liittyvät komplikaatiot olivat harvinaisia, mutta vähäisempiä tai ohittuvia oireita aiheuttaneita komplikaatioita todettiin useammin. Aivovaltimo-ohitusleikkaukset ovat erityisen vaativa hoitomuoto ja viime vuosina onkin suonensisäisillä virtausohjureilla hoidettu yhä enemmän komplekseja aneurysmia. Paras hoitomenetelmä tulisi valita tapauskohtaisesti ja punniten erilaisten aneurysman kompleksien ominaisuuksien aiheuttamaa kokonaishaastetta